Ocular solutions

ABSTRACT

Ocular solutions containing at least one macrolide antibiotic and/or mycophenolic acid provide anti-inflammatory, anti-cell proliferation, anti-cell migration, anti-angiogenesis, antimicrobial, and antifungal effects. In one embodiment, the solution is administered intraocularly after cataract surgery before insertion of a replacement intraocular lens, resulting in reduced posterior capsular opacification which may eliminate the need for a subsequent surgery. The solution may be one that is invasively administered, for example, an irrigation or volume replacement solution containing at least one macrolide antibiotic such as tacrolimus, sirolimus, everolimus, cyclosporine, and ascomycin, or mycophenolic acid. The solution may be one that is non-invasively or topically administered in the form of drops, ointments, gels, creams, etc. and may include eye lubricants and contact lens solutions.

This application is a Continuation of U.S. patent application Ser. No.10/667,161 filed Sep. 19, 2003.

FIELD OF THE INVENTION

The invention is directed to ocular solutions containing macrolideantibiotics to provide anti-inflammatory and other beneficial effects.

BACKGROUND

The eye is naturally bathed internally and externally by ocular fluids.The external portion of the eye is lubricated by lacrimal fluids(tears). The internal portion of the eye has two fluid-containingchambers: the anterior chamber contains the aqueous humor or aqueous,and the posterior chamber contains the vitreous humor or vitreous.

Various conditions require the need to introduce fluids into or on thesurface of the eye to replace or replenish naturally occurring fluids.The loss of naturally occurring ocular fluids may be due to normalaging, pathological conditions, surgical intervention, etc. For example,during ocular surgery surgery, the vitreous is frequently removed andmust thereafter be replaced. Commercially available irrigating solutionsare often used to replace some or all of the vitreous, such asirrigating solutions infused to replace the vitreous removed duringvitrectomy and thereby to maintain the shape of the globe. Thecomposition and other properties of these solutions may affect thesurgical outcome for the patient, for example, a solution may affect theclarity of the cornea and lens, which may result in decreased visualacuity. Additionally, swelling of the cornea during vitrectomy may beinfluenced by components of the irrigating solution. Other conditionssuch as dry eye disease result in decreased external lubrication, andtopical solutions such as eye drops are often used to provide relief.Wash solutions are used topically to remove foreign material from theexternal surface of the eye and invasively to clear the cornea and otherstructures during surgery.

Ocular solutions, for introduction into the eye and/or topicalapplication, with improved properties are desirable. The inventiondescribes such compositions and method of using the compositions.

SUMMARY OF THE INVENTION

A substitute for an intraocular irrigating, wash, or volume replacementsolution is disclosed. The solution contains a concentration in therange from about 1 ng/ml to about 200 μg/ml of a macrolide antibioticand/or mycophenolic acid. This provides beneficial properties, such asreducing inflammation at a surgical site (anti-inflammatory effect),inhibiting cell migration and cell proliferation (anti-proliferative andanti-migratory effects), inhibiting the growth of new blood vessels atthe site of an ocular tumor (anti-angiogenic effect), reducing thegrowth of bacteria, fungi, etc. (anti-microbial and anti-fungaleffects). Its anti-inflammatory effect desirably occurs without anincrease in intraocular pressure, which may occur when steroids areadministered to control ocular inflammation. Such a composition may beused in patients undergoing ocular surgery such as cataract surgery,retinal repair, etc.

The macrolide and/or mycophenolic acid can be added to a commerciallyavailable ocular solution, or can be formulated with an ocular solution.The macrolide antibiotic can be tacrolimus, cyclosporine, sirolimus,everolimus, ascomycin, erythromycin, azithromycin, clarithromycin,clindamycin, lincomycin, dirithromycin, josamycin, spiramycin,diacetyl-midecamycin, tylosin, roxithromycin, ABT-773, telithromycin,leucomycins, and lincosamide. It can be formulated in an inert matrix, acapsule, a liposome, etc. It can be inserted, injected, or implantedwithin a specific site of the eye (e.g., within the lens capsule), orapplied generally to clear or wash a surgical field.

In one embodiment, the inventive ocular composition is administered to apatient undergoing cataract surgery. The solution, containing aconcentration in the range from about 20 μg/ml to about 200 μg/ml of amacrolide antibiotic and/or mycophenolic acid is introduced within thecapsule of the lens after the diseased lens has been removed and beforethe replacement lens is inserted. Macrospheres or macrocapsules of themacrolide antibiotic and/or mycophenolic acid can be implanted withinthe capsule in an alternate embodiment. This can be used to reduceopacification of the posterior capsule, which is a common problemfollowing cataract surgery.

An implantable lens which retains at least one of a macrolide antibioticor mycophenolic acid is also disclosed. This system provides areplacement lens ready for surgical implantation in a patient undergoingcataract surgery, with the lens containing a concentration of amacrolide antibiotic and/or mycophenolic acid. When the lens isimplanted within the lens capsule of a patient's eye, the antibiotic ormycophenolic acid is then released to provide therapeutic effects to thecapsule (e.g., anti-cell proliferative effects, anti-inflammatoryeffects, etc).

These and other advantages of the invention will be apparent in light ofthe following figures and detailed description.

DETAILED DESCRIPTION

An ocular solution containing one or more macrolide antibiotics and/ormycophenolic acid is disclosed. The ocular solution may be anyphysiologically compatible ocular solution. It may used externally (e.g.topical administration) or internally (e.g. invasive administration.)

Ocular solutions are frequently administered to a patient followingocular surgery; macrolide antibiotics in these solutions desirablyprovide anti-inflammatory effects which aid in post-surgical recovery.In addition, macrolide antibiotics provide these anti-inflammatoryeffects without an increase in intraocular pressure that oftenaccompanies administration of steroids to post-surgical patients tocontrol inflammation.

Macrolide antibiotics also reduce cell proliferation and cell migration.This may promote the healing process, and may also provide ananti-angiogenesis effect to retard the proliferation and/or growth ofnew vessels. As one example, controlling the growth of new blood vesselsis a way to control proliferation of tumor cells; macrolide antibioticsin an ocular solution may be helpful in controlling ocular neoplasms ortumors. As another example, the solutions may be used to in patientshaving diseases characterized by abnormal angiogenesis, such as certaintypes of cancers, diabetic retinopathy, and sickle cell retinopathy, inwhich an anti-angiogenesis effect is desirable. Macrolide antibioticsalso provide antimicrobial and antifungal properties to ocularsolutions.

It will be appreciated that the inventive composition need not be in thephysical form of a true solution, but instead may be a suspension, anemulsion, a gel, etc. It may also encompass the macrolide antibioticand/or mycophenolic acid in the form of microspheres, microvesicles,microcapsules, and/or liposomes. In addition, ocular solutions fortopical application may take the form of any of the above, as well as anointment, a cream, a lotion, etc. Thus, the term solution is used forconvenience but encompasses other physical states. It will also beappreciated that the macrolide antibiotics may be included in theformulation for preparing an ocular solution, or may be added in dryform or in concentrated form to an already prepared ocular solution.

The ocular solution may be one that is used as an ocular irrigatingsolution and/or as a volume replacement solution during ocular surgery.It is thus a substitute for an ocular fluid, such as the vitreous,and/or a substitute for a commercially available irrigating solutionthat may be used during ocular surgery. It may also be one that is usedtopically, and thus encompasses eye drops, eye wash solutions, andcontact lens solutions. It may be used in over the counter (OTC) ocularsolutions for topical application, for example, in ocular solutions suchas artificial tears or lubricants. One commercially available ophthalmiclubricant is Viva-Drops®, available from Vision Pharmaceuticals, Inc.(Mitchell S. Dak.). The invention includes but is not limited to thisparticular embodiment.

In one embodiment, an ocular solution contains at least one macrolideantibiotic and/or mycophenolic acid and is used for intraocularadministration. Intraocular administration indicates an invasive routeof administration, compared to a topical route of administration. Inthis embodiment, the ocular solution containing the macrolideantibiotic(s) may be an irrigating solution, a volume replacementsolution, and/or a wash solution.

The inventive composition may be used in physiologic ophthalmicirrigating solutions. One example is Balanced Salt Solution (BSS®,available from Alcon Laboratories, Randburg, South Africa), containingper ml 0.64% sodium chloride, 0.075% potassium chloride, 0.048% calciumchloride, 0.03% magnesium chloride, 0.39% sodium acetate, and 0.17%sodium citrate dihydrate, as well as sodium hydroxide and/orhydrochloric acid to adjust pH, and water for injection. Another exampleis Ocular Irrigation Solution® (Allergan, Irvine Calif.). Anotherexample is lactated Ringer's solution. Another example is a normalsaline solution. Another example is normal saline adjusted to pH 7.4with sodium bicarbonate.

The inventive composition may also be used in ophthalmic volumereplacement solutions. For example, it may be introduced into theposterior chamber of the eye to replace the vitreous that is removedduring the repair of retinal disorders (vitrectomy).

The inventive composition may also be introduced into the lens capsuleduring cataract surgery. A cloudy and discolored lens, referred to as acataract, causes decreased vision and treatment requires that the lensbe surgically removed. Cataract surgery usually involvesphacoemulsification of the diseased lens inside the capsule, aspirationof the emulsified material, irrigation, and insertion of a replacementintraocular lens (IOL) within the capsule.

Following cataract surgery, there is frequently opacification of theposterior capsule which also diminishes visual acuity. Surgicaltechniques to minimize posterior capsule opacification have variablesuccess, and patients undergoing cataract surgery may require anadditional procedure to attend to the capsular opacification thatsubsequently occurs.

A complication for IOL implantation is post-operative opacification.This occurs as a result of lens epithelial cells (LEC) which migratearound the posterior capsule, and may be due to lack of maximum contactbetween the IOL optic and the posterior capsule. In children treated forpediatric cataracts, leaving the posterior capsule intact after IOLimplantation predisposes them to secondary cataract formation and severevisual axis opacification (VAO). This usually requires surgery toprevent VAO and an anterior vitrectomy to maintain a clear visual axisduring pediatric IOL surgery. Thus, reduction in the extent of cellmigration and/or cell proliferation following cataract surgery isdesirable.

In this embodiment of the invention, an irrigating or volume replacementsolution containing at least one macrolide antibiotic and/ormycophenolic acid is administered to the capsule with or beforeinserting the replacement lens. Without being bound by any theory, themacrolide antibiotic and/or mycophenolic acid may reduce posteriorcapsular opacification and visual axis opacification by its inhibitoryeffect on ocular cell proliferation and cell migration.

The macrolide antibiotic and/or mycophenolic acid can also be providedon a lens that will be implanted within a patient's eye. These lensesinclude any IOL used to replace a patient's diseased lens followingcataract surgery, including but not limited to those manufactured byBausch and Lomb (Rochester N.Y.), Alcon (Fort Worth Tex.), Allergan(Irvine Calif.), and Advanced Medical Optics (Santa Ana Calif.). Thesystem provides a therapeutic replacement lens ready for surgicalimplantation in a patient. When the lens is implanted within the lenscapsule, the antibiotic and/or mycophenolic acid provides therapeuticeffects (e.g., anti-cell proliferative effects, anti-inflammatoryeffects, etc) to the eye.

A concentration of the macrolide antibiotic and/or mycophenolic acidwithin the capsule is provided to achieve the previously describedtherapeutic effect. In one embodiment, the concentration ranges fromabout 20 μg/ml to about 2000 μg/ml. In another embodiment, theconcentration ranges from about 200 μg/ml to about 2000 μg/ml. Inanother embodiment, the concentration ranges from about 20 μg/ml toabout 200 μg/ml.

The IOL may be made of hydrophobic or hydrophilic material. The type ofmaterial determines whether the IOL cannot fold, is rigid and requires alarge incision to insert, or is flexible to allow the lens to be rolled,compressed, or folded for insertion through a smaller incision. The mostcommon materials used in IOL are various chemical modifications ofsilicon, hydrophobic acrylates, hydrophobic acrylates, and hydrogelswhich contain water to impart gel-like characteristic to the material.Each of these can be formulated or treated to contain a solutioncontaining a macrolide antibiotic and/or mycophenolic acid.

In one embodiment, the implantable IOL is packaged in an ophthalmicallyacceptable medium which contains the macrolide antibiotic and/ormycophenolic acid. For example, a porous hydrogel lens (e.g.,Hydroview®, Bausch & Lomb Surgical, Rochester N.Y.) retains themacrolide antibiotic and/or mycophenolic acid within the pores. Uponinsertion/implantation of the lens into the lens capsule, the macrolideantibiotic and/or mycophenolic acid is released into the capsule. Aslow-release system provides extended therapy over the post-surgicalrecovery period as the actives are slowly released through the porouselements.

In another embodiment, the implantable lens is coated to provide themacrolide antibiotic and/or mycophenolic acid. This embodiment may beused with a non-hydrogel hydrophilic lens, a hydrophobic lens, a lensmade from an acrylic material (e.g., AcrySof®; Alcon, Fort Worth Tex.;Sensar®; Advanced Medical Optics, Santa Ana Calif.), a silicone lens(e.g., CeeOn®, Pharmacia & Upjohn Company, Pickering Ohio), etc. Coatingand/or incorporation procedures that may be used are known to oneskilled in the art; for example, as disclosed in U.S. Pat. Nos.6,238,799; 6,179,817; 6,306,422; and 6,258,856, each of which isincorporated by reference herein in its entirety. The macrolideantibiotic and/or mycophenolic acid may be added to the storage solutionduring packaging of the IOL, or may be incorporated into the manufactureof the IOL. For example, the macrolide antibiotic and/or mycophenolicacid may be incorporated into either or both the hydration fluid in theformation of a hydrophilic or hydrogel IOL, or in the storage solution.In another example, the macrolide antibiotic and/or mycophenolic acidmay be in an acceptable encapsulated form in a hydrogel IOL for extendedlong term release.

The inventive composition may also be used as an ocular wash solution,for example, to clear the surgical field during intraocular surgery.

In each of the above embodiments, any macrolide antibiotic alone or incombination may be used. Embodiments of the invention include variousocular-compatible concentrations of the macrolide antibiotic(s) and/ormycophenolic acid sufficient to provide an anti-inflammatory,anti-proliferative, anti-cell migration, anti-fungal, etc. effect.Concentrations of the macrolide antibiotic may depend upon the use forthe composition, as is known to one skilled in the art. Thus, theinvention is not limited to a specific concentration of macrolideantibiotic. In general, the macrolide antibiotic is present in theocular solution at concentrations ranging from about 1 ng/ml to about200 μg/ml. In one embodiment, the macrolide antibiotic is present in theocular solution at a concentration of about 1 μg/ml. For use to reducecapsular opacification following cataract surgery, concentrationsranging from about 1 μg/ml to about 200 μg/ml, or from about 20 μg/ml toabout 200 μg/ml, may be used. The properties of the macrolide- and/ormycophenolic acid-containing ocular solution are compatible with oculartissues.

The macrolide antibiotic may be formulated with a viscoelastic substancesuch as hyaluranic acid, or may be contained in microspheres,macrospheres, microvesicles, macrovesicles, microcapsules,macrocapsules, liposomes, etc., as described in co-pending U.S. patentapplication Ser. No. 10/631,143 which is expressly incorporated byreference herein in its entirety. This embodiment may be used withsolutions administered to prevent capsular opacification followingcataract surgery, as previously described.

Liposomes may be prepared from dipalmitoyl phosphatidylcholine (DPPC),for example, from egg phosphatidylcholine (PC), a lipid with a low heatof transition. Liposomes are made using standard procedures as known toone skilled in the art. The macrolide antibiotic(s), in amounts rangingfrom nanogram to microgram quantities, is added to a solution of egg PC,and the lipophilic drug binds to the liposome.

A time-release drug delivery system may be administered intraocularly toresult in sustained release of the macrolide antibiotic(s) over a periodof time. The formulation may be in the form of a vehicle, such as amicro- or macro-capsule or matrix of biocompatible polymers such aspolycaprolactone, poly(glycolic) acid, poly(lactic) acid, polyanhydride,or lipids that may be formulated as microspheres or liposomes. Amacroscopic formulation may be administered through a needle, or may beimplanted by suturing within the eye, for example, within the lenscapsule. As an illustrative example, sirolimus may be mixed withpolyvinyl alcohol (PVA), the mixture then dried and coated with ethylenevinyl acetate, then cooled again with PVA. In a formulation forintraocular administration, the liposome capsule degrades due tocellular digestion providing a slow release drug delivery system,allowing the patient a constant exposure to the drug over time.

Delayed or extended release properties may be provided through variousformulations of the vehicle (coated or uncoated microsphere, coated oruncoated capsule, lipid or polymer components, unilamellar ormultilamellar structure, and combinations of the above, etc.). Othervariables may include the patient's pharmacokinetic-pharmacodynamicparameters (e.g., body mass, gender, plasma clearance rate, hepaticfunction, etc.). The formulation and loading of microspheres,microcapsules, liposomes, etc. and their ocular implantation arestandard techniques known by one skilled in the art, for example, theuse a ganciclovir sustained-release implant to treat cytomegalovirusretinitis, disclosed in Vitreoretinal Surgical Techniques, Peyman etal., Eds. (Martin Dunitz, London 2001, chapter 45); Handbook ofPharmaceutical Controlled Release Technology, Wise, Ed. (Marcel Dekker,New York 2000), the relevant sections of which are incorporated byreference herein in their entirety.

Examples of macrolide antibiotics that may be used for intraocularadministration include, but are not limited to, tacrolimus, CyclosporinA, sirolimus, ascomycin, and everolimus. Tacrolimus (Prograf®, FujisawaHealthcare, Deerfield, Ill.; FK-506), a macrolide immunosuppressantproduced by Streptomyces tsukubaensis, is a tricyclo hydrophobiccompound that is practically insoluble in water, but is freely solublein ethanol and is very soluble in methanol and chloroform. It isavailable under prescription as either capsules for oral administrationor as a sterile solution for intravenous administration. The solutioncontains the equivalent of 5 mg anhydrous tacrolimus in 1 ml of polyoxyl60 hydrogenated castor oil (HCO-60), 200 mg, and dehydrated alcohol(USP, 80.0%^(v/v)), and must be diluted with a solution of 0.9% NaCl or5% dextrose before use.

Tacrolimus has been used for topical administration to treat a varietyof dermatoses. Topical administration of tacrolimus at doses rangingfrom 0.03%-0.3% resulted in significant clinical improvement in atopicdermatitis after 2-3 weeks treatment, and tacrolimus treatment of otherdermatologic diseases shows promise. Tacrolimus, like cyclosporine,blocks the signal transduction pathway needed to induce interleukin-2gene expression and thereby activate T lymphocytes. In addition tosuppressing T cell activation, tacrolimus inhibits anti-IgE-triggeredhistamine release and inhibits prostaglandin D2 synthesis in human skinmast cells. While oral administration produces limiting adverse effects(systemic immunosuppression, infection, neural toxicity, nephrotoxicity,and hypertension), topical administration for treatment of dermatoses atconcentrations up to 0.3% showed no significant difference in effectsbetween treated and control groups. In addition, tacrolimus is welltolerated locally and only occasionally causes mild irritation.

The use of tacrolimus as a specific medicament for treatment of oculardisease has been disclosed in U.S. Pat. No. 6,489,335 and co-pendingU.S. patent application Ser. No. 10/247,220, each of which is expresslyincorporated by reference herein in its entirety. For example,tacrolimus may be contained in an aqueous-based cream excipient fortopical application, or it may be injected intraocularly, or it may beadministered surgically as an ocular implant.

Cyclosporin A (cyclosporine, topical formulation Arrestase®, AllerganInc.) is a cyclic peptide produced by Trichoderma polysporum. It isavailable commercially, for example, from Sigma-Aldrich (St. Louis,Mo.). It is an immunosuppressant and acts in a particular subset of Tlymphocytes, the helper T cells. Cyclosporin A exerts animmunosuppressant effect by inhibiting production of the cytokineinterleukin 2. Each of Cyclosporin A and tacrolimus, anotherimmunosuppressant, produce significant renal and hepatic toxicity wheneach is administered systemically; because of this toxicity, they arenot administered together.

Cyclosporin A has been administered to treat ocular conditions such asglaucoma, corticosteroid-induced ocular hypertension, allograftrejection, infections, and ocular surface disease. Its use has beenreported for the treatment of uveitis (inflammation of the uvea) bytopical, intravitreal or systemic administration with doses of 0.05%,0.1%, and 0.5%. Cyclosporin A has good penetration into the cornea butnot into the anterior chamber, and does not increase intraocularpressure or cause cataracts. Its known toxicity had previously limitedits use for other ocular diseases.

The use of Cyclosporin A as a specific medicament for treatment ofocular disease with reduced toxicity has been described in co-pendingU.S. patent application Ser. No. 10/289,772, which is expresslyincorporated by reference herein in its entirety.

Sirolimus, also known as rapamycin, RAPA, and Rapamune®, is a trienemacrolide antibiotic derived from Streptomyces hydroscopicus andoriginally developed as an antifungal agent. Subsequently, it has shownanti-inflammatory, anti-tumor, and immunosuppressive properties.Ascomycin, also known as pimecrolimus, Immunomycin, and FR-900520, is anethyl analog of tacrolimus and has strong immunosuppressant properties.It inhibits Th1 and Th2 cytokines, and preferentially inhibitsactivation of mast cells, and is used to treat contact dermatitis andother dermatological conditions. Sirolimus and ascomycin arecommercially available, e.g., A.G. Scientific, Inc. (San Diego, Calif.).

Regarding its immunosuppressive potential, sirolimus has some synergeticeffect with Cyclosporin A. It has been reported that sirolimus has adifferent mode of action compared to Cyclosporin A and tacrolimus. Allthree agents are immunosuppresants which affect the action of immunecell modulators (cytokines), but do not affect the immune cellsthemselves. However, while all three agents affect immune cellmodulators, they do so differently: Cyclosporin A and tacrolimus preventsynthesis of cytokine messengers, specifically interleukin-2, whilesirolimus acts on cytokine that has already been synthesized, preventingit from reaching immune cells.

Sirolimus inhibits inflammation by acting on both T-lymphocytes anddendritic cells. The latter are the first cells to recognize antigens.Sirolimus blocks the growth of dendritic cells and a number of othercells, such as tumors and endothelial cells, which are activated by thetumor cell releasing vascular endothelial growth factor (VEGF). VEGF isa central regulator of angiogenesis (formation of new blood vessels frompre-existing vessels) and vasculogenesis (development of embryonicvasculature through an influence on endothelial cell differentiation andorganization). Diseases that are characterized by abnormal angiogenesisand vasculogenesis, such as some cancers and some ocular diseases, mayshow abnormal production of VEGF. Thus, control of VEGF function may beone means to control or treat these diseases. Sirolimus has also beenused in the prevention of smooth muscle hyperplasia after coronary stentsurgery. The use of sirolimus and ascomycin as specific medicaments fortreatment of ocular disease has been disclosed in co-pending U.S. patentapplication Ser. No. 10/631,143, which is expressly incorporated byreference herein in its entirety.

Everolimus, also known as RAD-001, SCZ RAD, Certican™ (Novartis, BaselSwitzerland), is an analog of sirolimus but is a new and distinctchemical entity. It is an oral immunosuppressant that inhibits growthfactor-induced cell proliferation and thus reduces acute organ rejectionand vasculopathy, the proliferation of smooth muscle cells in theinnermost wall of grafts that restricts blood supply.

Mycophenolic acid (MPA) is the active compound formed following theadministration of mycophenolate mofetil (MMF). The prodrug is themorpholinoethyl ester of mycophenolic acid. Mycophenolic acid is anantileukemic and immunosuppressant agent used in patients undergoingchemotherapy for cancer and in transplant recipients.

The addition of these agents, either alone or in combination, toinvasively administered ocular solutions according to the inventionprovides beneficial anti-inflammatory, anti-proliferative, anti-cellmigration, antimicrobial, and antifungal properties.

It will be appreciated that the invention encompasses the use ofmacrolide antibiotics and/or mycophenolic acid, in addition to thosepreviously described, in an ocular solution. These include, for example,the known antibiotics erythromycin and its derivatives such asazithromycin and clarithromycin, lincomycin, dirithromycin, josamycin,spiramycin, diacetyl-midecamycin, tylosin, and roxithromycin. Theinvention also includes new macrolide antibiotic scaffolds andderivatives in development, including but not limited to the ketolidesABT-773 and telithromycin as described by Schonfeld and Kirst (Eds.) inMacrolide Antibiotics, Birkhauser, Basel Switzerland (2002); macrolidesderived from leucomycins, as described in U.S. Pat. Nos. 6,436,906;6,440,942; and 6,462,026 assigned to Enanta Pharmaceuticals (WatertownMass.); and lincosamides.

In addition to the above described uses, the invention comprises ocularsolutions for topical (non-invasive) ocular administration witheverolimus, erythromycin, azithromycin, clarithromycin, lincomycin,dirithromycin, josamycin, spiramycin, diacetyl-midecamycin, tylosin,roxithromycin, and mycophenolic acid, as well as the previouslydescribed new macrolide antibiotic scaffolds and derivatives indevelopment, including but not limited to the ketolides ABT-773 andtelithromycin, macrolides derived from leucomycins, and lincosamides.

The macrolide antibiotics are included with ocular solutions for anyuse. The macrolide antibiotic may be added together or separately asindividual components in the preparation of an ocular solution.Alternatively, a solution of the macrolide antibiotic may be preparedand then added to the ocular solution. The solutions may be commercialirrigating solutions that contain other known components, such asvarious anions and cations, buffers to regulate pH, adenosine, calcium,glucose, bicarbonate, dextrose, dextran 40 (a low molecular weightcolloidal osmotic agent), gentamicin, dexamethasone, selenium, zinc, andgluconide. The macrolide antibiotic may be added to commercial ocularlubricating solutions, such as artificial tears. The macrolideantibiotic may be included with commercial ocular wash solutions. Themacrolide antibiotic may be included with contact lens wash, rinse, andwetting solutions. Any solution for ocular administration, eitheradministration to the exterior surface of the eye or to one of theinterior chambers of the eye, may contain the macrolide antibiotic.

The invention is also not limited to human use, and encompasses the useof ocular solutions containing at least one macrolide antibiotic forveterinary use. For example, lincosamides have been used in animals; anocular solution containing a lincosamide may be used as a veterinaryirrigation solution, volume replacement solution, topical wash orlubricant solution, etc.

The invention provides general purpose ocular solutions in the form ofeye drops, eye washes, eye irrigating solutions, volume replacementsolutions, contact lens solutions, etc. that contain one or more of theabove macrolide antibiotics. In various embodiments, the ocular solutionmay be in single or multi-dose containers (e.g., 10 ml, 20 ml, 30 ml,500 ml).

Other variations or embodiments of the invention will also be apparentto one of ordinary skill in the art from the above figures anddescriptions. Thus, the forgoing embodiments are not to be construed aslimiting the scope of this invention.

1. A composition comprising a solution for intraocular administrationcontaining a concentration in the range between about 1 ng/ml to about200 μg/ml of at least one of a macrolide antibiotic or mycophenolic acidas a substitute for an ocular or operative fluid.
 2. The composition ofclaim 1 wherein the macrolide antibiotic is at a concentration of about1 μg/ml.
 3. The composition of claim 1 wherein the macrolide antibioticis at a concentration in the range of about 1 μg/ml to about 20 μg/ml.4. The composition of claim 1 wherein the macrolide antibiotic is at aconcentration in the range of about 20 μg/ml to about 200 g/ml.
 5. Thecomposition of claim 1 wherein the solution is selected from at leastone of an irrigation solution, a volume replacement solution, and a washsolution.
 6. The composition of claim 1 wherein the macrolide antibioticis at least one of tacrolimus, cyclosporine, sirolimus, everolimus,ascomycin, erythromycin, azithromycin, clarithromycin, clindamycin,lincomycin, dirithromycin, josamycin, spiramycin, diacetyl-midecamycin,tylosin, roxithromycin, ABT-773, telithromycin, leucomycins, andlincosamide.
 7. The composition of claim 1 wherein the macrolideantibiotic or mycophenolic acid is formulated as at least one of amicrocapsule, a microsphere, a microvesicle, and a liposome.
 8. Thecomposition of claim 1 wherein the macrolide antibiotic or mycophenolicacid is provided to a prepared ocular solution.
 9. The composition ofclaim 1 wherein the macrolide antibiotic or mycophenolic acid isprovided in formulating an ocular solution.
 10. A therapeutic methodcomprising providing to an eye of a patient an ocular solutioncontaining at least one of a macrolide antibiotic or mycophenolic acidat a concentration in the range between about 1 ng/ml to about 200 μg/mlto provide a therapeutic effect.
 11. The method of claim 10 wherein themacrolide antibiotic or mycophenolic acid provides at least one of ananti-inflammatory effect, an anti-cell proliferation effect, ananti-cell migration effect, an anti-angiogenesis effect, anantimicrobial effect, and an antifungal effect.
 12. The method of claim10 wherein the macrolide antibiotic or mycophenolic acid provides ananti-inflammatory effect without increased intraocular pressure.
 13. Themethod of claim 10 wherein the macrolide antibiotic or mycophenolic acidprovides an anti-angiogenic effect in a patient with an ocular tumor, apatient with diabetes, or a patient with sickle cell anemia.
 14. Themethod of claim 10 wherein the macrolide antibiotic or mycophenolic acidis at a concentration of about 1 μg/ml.
 15. The method of claim 10wherein the macrolide antibiotic or mycophenolic acid is at aconcentration ranging from about 1 ng/ml to about 20 μg/ml.
 16. Themethod of claim 10 wherein the macrolide antibiotic or mycophenolic acidis at a concentration ranging from about 20 μg/ml to about 200 μg/ml.17. A therapeutic method comprising intraocularly administering to apatient undergoing cataract surgery an ocular solution containing atleast one of a macrolide antibiotic or mycophenolic acid at aconcentration in the range from about 20 μg/ml to about 200 μg/ml withina lens capsule prior to insertion of a replacement intraocular lens. 18.The method of claim 17 wherein the solution reduces opacification of theposterior capsule.
 19. The method of claim 17 wherein the macrolideantibiotic is formulated as at least one of a liposome, a macrosphere, amicrosphere, a macrocapsule, a microcapsule, a macrovesicle, and amicrovesicle.
 20. The method of claim 17 wherein the macrolideantibiotic or mycophenolic acid is at a concentration in the range ofabout 20 μg/ml to about 200 μg/ml.
 21. The method of claim 19 whereinthe macrolide antibiotic or mycophenolic acid is implanted within thecapsule.
 22. An article comprising an implantable ocular replacementlens in a solution containing a concentration of a macrolide antibioticor mycophenolic acid sufficient to provide the lens with at least oneeffect selected from anti-cell proliferation, anti-cell migration,anti-inflammatory, anti-angiogenesis, antimicrobial, and antifungal. 23.The article of claim 22 wherein the concentration is in the rangebetween about 20 μg/ml to about 2000 μg/ml.
 24. The article of claim 22wherein the concentration is the range between about 20 μg/ml to about200 μg/ml.
 25. The article of claim 22 wherein the macrolide antibioticis at least one of tacrolimus, cyclosporine, sirolimus, everolimus,ascomycin, erythromycin, azithromycin, clarithromycin, clindamycin,lincomycin, dirithromycin, josamycin, spiramycin, diacetyl-midecamycin,tylosin, roxithromycin, ABT-773, telithromycin, leucomycins, andlincosamide.
 26. An article comprising an implantable ocular replacementlens containing at least one macrolide antibiotic or mycophenolic acid.27. The article of claim 26 wherein the antibiotic or mycophenolic acidis in a solution in which the lens is contained.
 28. The article ofclaim 26 wherein the lens is a porous hydrogel and the antibiotic ormycophenolic acid is within the pores of the hydrogel lens.
 29. Thearticle of claim 26 wherein the antibiotic or mycophenolic acid is in acoating on at least one lens surface.
 30. The article of claim 26wherein the lens is implanted in a lens capsule and the implanted lensreleases the antibiotic or mycophenolic acid in the lens capsule. 31.The article of claim 26 wherein the macrolide antibiotic is at least oneof tacrolimus, cyclosporine, sirolimus, everolimus, ascomycin,erythromycin, azithromycin, clarithromycin, clindamycin, lincomycin,dirithromycin, josamycin, spiramycin, diacetyl-midecamycin, tylosin,roxithromycin, ABT-773, telithromycin, leucomycins, and lincosamide. 32.An article comprising an implantable ocular lens in an opthalmicallyacceptable medium, the medium further comprising an effective anti-cellproliferative or anti-cell migratory concentration of at least onemacrolide antibiotic or mycophenolic acid.
 33. The article of claim 32wherein the concentration is in the range between about 20 μg/ml toabout 2000 μg/ml.
 34. The article of claim 32 wherein the concentrationis in the range between about 200 μg/ml to about 2000 μg/ml.
 35. Thearticle of claim 32 wherein the concentration is in the range betweenabout 20 μg/ml to about 200 μg/ml.
 36. The article of claim 32 whereinthe macrolide antibiotic is at least one of tacrolimus, cyclosporine,sirolimus, everolimus, ascomycin, erythromycin, azithromycin,clarithromycin, clindamycin, lincomycin, dirithromycin, josamycin,spiramycin, diacetyl-midecamycin, tylosin, roxithromycin, ABT-773,telithromycin, leucomycins, and lincosamide.